First Mark Smith Memorial Lecture given by Professor John Hardy

Yesterday February 14th we celebrated the life of Mark Smith, a friend and colleague of many present, including me. John Hardy, now back in the UK after 15 years in the US, delivered a noon lecture and also presented with others at a celebration of Mark’s life in the Amasa Stone Chapel in the afternoon.

Both events were also attended by Mark’s closest friend, mentor and colleague, George Perry, now a dean in Texas, who I also know well. His wife Gemma, as well as university dignitaries and colleagues, presented stories, words and music. The ceremony ended wonderfully with a lullaby Mark had sung to his two chip-off-the-old-block sons, played by Professor Richard Hanson on his banjo and sung by the audience so Mark could (almost) hear it.

In my opinion, we recreated the energetic spirit characteristic of Mark’s life including themes of family, soccer, drinking, mentoring, courage, and collaboration. George and John engaged in some friendly sparing even in the chapel since George and Mark were major critics of Hardy’s advocacy of the amyloid hypothesis. Mark would have liked that verbal give-and-take too. As we have expressed in this blog many times before, Danny and I find ourselves amongst the amyloid critics as well.

In the spirit of Mark and George’s criticisms of the amyloidologists, I offer this scientific update base on both personal conversation and John’s public address. John believes that the amyloid model works so well for the autosomal dominant forms that he wants to conduct a trial of an anti-amyloid drug in these rare patients.

Having worked with our mutual friend and colleague Martin Rossor in London surveying these families around the UK, I know the challenge such a trial would be. When would you start i.e. when someone if identified as having the gene without symptoms yet? Which drug would you use? What outcome measures would be best? How could you justify such a trial given the relatively few people affected by this condition? Perhaps it would be a large “proof of concept trial.”

John also provided more information on the variability of persons with these mutations. Those with APP and presenilin mutations differ with regards to age of onset, clinical features and distribution of pathology. Why should this be so if amyloid processing is to be blamed in all these autosomal dominant cases. And why should the clinical features and pathology vary even in members of the same family with the same genetic lesion? There is much we do not know, including as John pointed out, that we have no good understanding of what the normal amyloid related proteins do.

The relevance of amyloid is much less clear as Prof Hardy admits to the vast number of people with so-called sporadic Alzheimer’s disease without autosomal dominant genes. He almost agreed with Mark Smith, George and I that amyloid may be a factor but not primary.

He described new collaborative genetic studies of susceptibility genes where mechanism of response to inflammation and cholesterol metabolism may be involved. Other than Apo, a gene which affects risk for many conditions, the other genes appear to account for little of the variability in clinical features, however. It seems much more likely that sporadic “AD” is caused by many factors and not primarily by genes. Genes may well play a role, as one might expect, in how the body responds to the aging processes, such as inflammation and vascular dysfunction.

John began his talk by celebrating the spirit of science that invited controversy and skepticism. I sensed yesterday that that openness only goes so far. To challenge the scientific, and particularly the molecular genetic, approaches to chronic disease, is still not fully acceptable to the majority present. The idea that an intergenerational school promoting brain health and giving purpose and meaning to the lives of elders is not in the same league with this crowd. I felt an outsider, even though I have known many of the people present for decades.

But Mark’s courage to stand up to the dominant views and values in a field gives me courage. John ended by taking about his common North of England heritage with Mark (something I share by the way although Johns said he forgot I was British). Apparently being rude is acceptable as long as it is done in a spirit of comradeship (see House of Commons behavior for example). Anyway, he acknowledged that like Mark, I was playing a role being provocative, even though he did not seem to quite appreciate the provocation.

Some molecular types are also beginning to see the light, however. Konrad Beyreuther was one of the pioneering molecular biologists who once celebrated the power of science to eventually cure conditions such as AD. Now as Director of the Network Aging Research at Heidelberg University, he has come to conclude that molecular approaches are more limited than he had previously thought. With his permission, we quote him as saying “Molecules are more or less the same in all human brains. But human brains are not at all the same.” Konrad also told us that he now believes that the disease conceptions invented by scientifically-oriented doctors are of limited help to people who have cognitive impairment as they age.

With Mark and Konrad, I celebrate the power of science but also recognize its limitations. Both loved being scientists as I do, but knew the fallibilities of all of us as human beings. Rest-in-peace, Mark. You deserve it and inspired many of us to keep up the good fight down here.

Comments

Hello, never before pictures of what it is really like to live with dementia, probably of the alzheimer’s type and have to live day to day
with the cure pill pipeline never more than a few inches from your mouth! (sorry I couln’t figure out how to include pictures in a comment here, you will have to go to my blog to see the heart breaking pictures). But I think my obsersations are worth sharing, even if I can’t provide pictures for those of you who are visual learners.

Althought it was never my intention to belittle or make fun of the real beliefs and hopes of folks that there is such a thing as a “pipeline”, it has become clearer to me how we have all been
shaped/brain washed by this brilliant piece of public relations/marketing/fund raising flim flam.

There is no pipeline. There is no pipeline. Drug companies are throwing pills at us, and fortunately thanks to the FDA most all of
them never make it to our mouths. That does stop them from spending
literally millions of dollars promoting the trials int he media – just on the off chance one of them is actually statistically significant,
and even if it’s signifance is based on a sky scraper of playing cards rather than hard science, a consesus of experts in and out of the
business of Alzheimer’s research, and the National INstitute of Health.

If it takes another figment of someone one’s imagination – in this case mine to counteract the figment of someone one elses imagination
(the existance of a drug pipeline line) then so be it.

I just read an article promoting the need to hurry up and adopt the proposed new diagnositic criteria because there were so many promising drugs in the pipeline we had to be ready to diagnosis folks as near to the day of their birth as possible so we would know who might come down with alzheimer’s disease at some distant point in their lifes,
and thus we should start them on these new promising drugs the moment they fell out of the pipeline.

There is no pipeline. It is one of the “new myths of Alzheimer’s.” And guess who speaks most and loudest about this imaginary pipeline? And
guess what strategy, what means to an end promoting this myth support?

The next time you hear someone referring to “the pipeline” please consider pointing out to them the pipeline full of myths that run next to the pipeline full of pills.

I ran across your website a while back. I didn’t think much of it as I have seen many websites which claim to “know the real truth” behind diseases and I figured this was one such site. Boy was I wrong. I came across it again a few days ago doing a search for George Perry, whom I work with as an undergrad at the University of Texas, San Antonio.
Anyway, to make a long story short, I was talking with him today and he mentioned the name Peter Whitehouse. I didn’t think much of it as he drops many names in the course of a conversation. But I came across this site again tonight and there was the name Peter Whitehouse and I put two and two together. Anyway, I’m glad this website is here. Thank you. I hope to find the time to buy your book.

Thanks Tim and Richard. The tide is turning towards a broader view which is my opinion is both more scientific (open, evidence-based, and skeptical) and more ethical (less commercialism, conflict of interest and scientism). Peter